Having defined substantial lasting impacts of early childhood diarrhea on childhood physical and cognitive development and having launched a placebo-controlled trial in a cohort of favela children in whom informative long-term follow-up by an experienced surveillance team is now feasible, we are now poised to address the potential causality for these devastating effects that more than double the global diarrhea DALYs by assessing the impact of micronutrient interventions in long-term follow-up (work that complements our ongoing studies of their mechanisms in vitro and in an animal model) and by assessing the heritability and plausible genetic determinants of parasitic infections, overt symptoms, and their long-term impact on physical and cognitive development. Hence our broad, long-term objectives are to ameliorate the long-term developmental impact of early childhood diarrhea and parasitic infections by showing effective interventions and demonstrating potential genetic determinants of these enteric infections and their impact. Initial studies in vitro and in children suggest that zinc and potentially synergistic arginine are among key micronutrients for the repair of intestinal damage and absorptive function. Our specific aims are therefore to (1) Determine the effects of zinc (alone or in combination with vitamin A) on the long-term development of higher executive function in an ongoing randomized clinical trial and in a new intervention trial of arginine (with or without zinc or alanyl-glutamine) on diarrhea morbidity, nutritional status, cognitive development, and intestinal barrier function;and (2) Define plausible genetic determinants of genotype specific major enteric protozoan and enteroaggregative E. coli (EAEC) infections, overt diarrhea, intestinal inflammation, and long-term developmental sequelae using pedigree and candidate single nucleotide polymorphism analyses for which we already have seminal clues. Now that we are finding that the greatest impact is on semantic fluency in APOE4-negative individuals experiencing heavy diarrhea (and also knowing that APOE4 is associated with enhanced arginine transport in developing microglia), our most provocative unifying hypothesis is that zinc will improve cognitive function by improving absorption and nutritional status and that arginine may specifically protect the absorptive function, growth, and semantic fluency in APOE4-negative children experiencing heavy diarrhea burdens. This single project ICIDR renewal, focused upon our existing strengths and unique opportunities, will not only build clinical trial and molecular genetics tools at our collaborating site in Northeast Brazil (now in new expanded facilities), but it will also help further document causality and solutions that will drive policy to address the costly problem of diarrheal diseases, enteric parasitic infections, and their long-term sequelae.